Irosustat: Difference between revisions

'''Irosustat''' ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}; developmental code names '''STX-64''', '''667-coumate''', '''BN-83495'''; also known as '''oristusane''') is an [[oral administration|orally active]], [[irreversible inhibitor|irreversible]], [[nonsteroidal]] [[enzyme inhibitor|inhibitor]] of [[steroid sulfatase]] (STS) and member of the aryl sulfamate ester class of drugs<ref>{{cite journal | vauthors = Thomas MP, Potter BV | title = Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 19 | pages = 7634–7658 | date = October 2015 | pmid = 25992880 | pmc = 5159624 | doi = 10.1021/acs.jmedchem.5b00386 }}</ref> that was under development by Sterix Ltd and [[Ipsen]] for the treatment of [[hormone-sensitive cancer]]s such as [[breast cancer]], [[prostate cancer]], and [[endometrial cancer]] but has not yet been marketed.<ref name="AdisInsight">{{Cite web | url=http://adisinsight.springer.com/drugs/800020388 |title = Irosustat -| work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref><ref name="pmid21342037">{{cite journal | vauthors = Palmieri C, Januszewski A, Stanway S, Coombes RC | title = Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer | journal = Expert Review of Anticancer Therapy | volume = 11 | issue = 2 | pages = 179–183 | date = February 2011 | pmid = 21342037 | doi = 10.1586/era.10.201 | s2cid = 7253764 }}</ref> The drug<ref>{{cite journal | vauthors = Woo LL, Purohit A, Malini B, Reed MJ, Potter BV | title = Potent active site-directed inhibition of steroid sulphatase by tricyclic coumarin-based sulphamates | journal = Chemistry & Biology | volume = 7 | issue = 10 | pages = 773–791 | date = October 2000 | pmid = 11033081 | doi = 10.1016/S1074-5521(00)00023-5 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Woo LW, Ganeshapillai D, Thomas MP, Sutcliffe OB, Malini B, Mahon MF, Purohit A, Potter BV | display-authors = 6 | title = Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor Irosustat (STX64, BN83495) | journal = ChemMedChem | volume = 6 | issue = 11 | pages = 2019–2034 | date = November 2011 | pmid = 21990014 | pmc = 3262147 | doi = 10.1002/cmdc.201100288 }}</ref> was first designed and synthesized in the group of Professor [[Barry V. L. Potter|Barry V L Potter]] at the Department of Pharmacy & Pharmacology, [[University of Bath]], working together with Professor [[Michael J. Reed]] at [[Imperial College London|Imperial College]], London and its initial development was undertaken through the university spin-out company Sterix Ltd and overseen by Cancer Research UK ([[Cancer Research UK|CRUK]]). Results of the "first-in-class" [[clinical trial]] in breast cancer of an STS inhibitor in humans were published in 2006<ref>{{cite journal | vauthors = Stanway SJ, Purohit A, Woo LW, Sufi S, Vigushin D, Ward R, Wilson RH, Stanczyk FZ, Dobbs N, Kulinskaya E, Elliott M, Potter BV, Reed MJ, Coombes RC | display-authors = 6 | title = Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor | journal = Clinical Cancer Research | volume = 12 | issue = 5 | pages = 1585–1592 | date = March 2006 | pmid = 16533785 | doi = 10.1158/1078-0432.CCR-05-1996 | doi-access = }}</ref> and dose optimisation studies and further clinical data have been reported.<ref>{{cite journal | vauthors = Coombes RC, Cardoso F, Isambert N, Lesimple T, Soulié P, Peraire C, Fohanno V, Kornowski A, Ali T, Schmid P | display-authors = 6 | title = A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer | journal = Breast Cancer Research and Treatment | volume = 140 | issue = 1 | pages = 73–82 | date = July 2013 | pmid = 23797179 | doi = 10.1007/s10549-013-2597-8 | s2cid = 20060727 }}</ref>

In 2004 Sterix Ltd was acquired by Ipsen and Irosustat continued in development through formal academic-industry partnerships by Ipsen with the University of Bath and Imperial College. The drug reached [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s in women with hormone-dependent breast cancer and endometrial cancer prior to the discontinuation of its initial development by Ipsen as a monotherapy for endometrial cancer in women with advanced/metastatic or recurrent estrogen-receptor positive endometrial cancer after a futility analysis of trial data.<ref name="AdisInsight" /><ref name="AvendanoMenendez2015">{{cite book|author1 vauthors =Carmen Avendano C, Menendez JC |author2 chapter =J. CarlosAnticancer Drugs that Modulate Hormone Action Menendez|title=Medicinal Chemistry of Anticancer Drugs| chapter-url = https://books.google.com/books?id=VEibBwAAQBAJ&pg=PA105|date=11 June 2015|publisher=Elsevier Science|isbn=978-0-444-62667-7|pages=105–}}</ref> Results published in 2017 showed clinical activity and a good safety profile for Irosustat, with 36% of patients on Irosustat alive without progression at 6 months; 11% showed responses and there was more stable disease noted (47%) compared to the current therapy (32%), the progestin [[megestrol acetate]] (MA).<ref>{{cite journal | vauthors = Pautier P, Vergote I, Joly F, Melichar B, Kutarska E, Hall G, Lisyanskaya A, Reed N, Oaknin A, Ostapenko V, Zvirbule Z, Chetaille E, Geniaux A, Shoaib M, Green JA | display-authors = 6 | title = A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer | journal = International Journal of Gynecological Cancer | volume = 27 | issue = 2 | pages = 258–266 | date = February 2017 | pmid = 27870712 | doi = 10.1097/IGC.0000000000000862 | s2cid = 3430946 | url = https://lirias.kuleuven.be/handle/123456789/558056 }}</ref> However, overall there were no statistically significant differences between Irosustat and the current standard of care MA in response and survival rates. It also reached a phase I trial in the US for prostate cancer, being safe and well tolerated in male patients with castration-resistant prostate cancer and ongoing androgen deprivation therapy. Pharmacodynamic proof of concept was demonstrated with Irosustat effecting nearly complete STS inhibition at three doses, and in all patients there was notable suppression of endocrine parameters.<ref>{{Cite journal|last vauthors = Denmeade|first= S, George D, Liu G, Peraire C, Geniaux A, Baton F, Ali T &, Chetaille E |date=2011|title=2011 A phase I pharmacodynamics dose escalation study of steroid sulphatase inhibitor Irosustat in patients with prostate cancer.|journal=European Journal of Cancer|volume=47|pages=S499 |doi=10.1016/S0959-8049(11)71998-0}}</ref> The development of Irosustat has continued with clinical trials overseen by CRUK designed to explore its activity in early breast cancer (IPET trial) <ref>{{cite journal | vauthors = Palmieri C, Szydlo R, Miller M, Barker L, Patel NH, Sasano H, Barwick T, Tam H, Hadjiminas D, Lee J, Shaaban A, Nicholas H, Coombes RC, Kenny LM | display-authors = 6 | title = IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer | journal = Breast Cancer Research and Treatment | volume = 166 | issue = 2 | pages = 527–539 | date = November 2017 | pmid = 28795252 | pmc = 5668341 | doi = 10.1007/s10549-017-4427-x }}</ref> and also in combination with an aromatase inhibitor (AI) (IRIS trial).<ref>{{cite journal | vauthors = Palmieri C, Stein RC, Liu X, Hudson E, Nicholas H, Sasano H, Guestini F, Holcombe C, Barrett S, Kenny L, Reed S, Lim A, Hayward L, Howell S, Coombes RC | display-authors = 6 | title = IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients | journal = Breast Cancer Research and Treatment | volume = 165 | issue = 2 | pages = 343–353 | date = September 2017 | pmid = 28612226 | pmc = 5543190 | doi = 10.1007/s10549-017-4328-z }}</ref> The multicentre IRIS trial, an open-label phase II clinical study, explored the clinical value of adding an STS inhibitor in addition to a first-line AI in patients with advanced breast cancer and enrolled postmenopausal women with [[Hormone receptor positive breast tumor|ER+]] locally advanced or metastatic breast cancer who had benefited from a first-line AI but were subsequently progressing. The IPET trial was a pre-surgical window-of-opportunity study, assessing Irosustat for the first time in ER+ early breast cancer and recruiting postmenopausal women with untreated early disease. Importantly, these data are the first to demonstrate clinical activity of Irosustat in early breast cancer, albeit in a small patient population. The results of both trials were published in 2017, showing evidence of clinical benefit and underpinning the scientific concept of STS inhibition. Larger studies are now required. Irosustat was also evaluated as a combination therapy with an oral [[epidermal growth factor receptor]] [[tyrosine kinase inhibitor]] for the treatment of [[Non-Small Cell Lung Cancer]] Patients.<ref>{{Cite web|title=A Pilot Study of a Steroid Sulphatase Inhibitor (BN83495) in Patients Receiving an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) for the Treatment of Non-Small Cell Lung Cancer (NSCLC)|url=https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336296|website=Australian New Zealand Clinical Trials Registry}}</ref> Clinical development continues and the current status was reviewed in 2018.<ref>{{cite journal | vauthors = Potter BV | title = SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects | journal = Journal of Molecular Endocrinology | volume = 61 | issue = 2 | pages = T233–T252 | date = August 2018 | pmid = 29618488 | doi = 10.1530/JME-18-0045 | doi-access = free }}</ref>